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Medicinal Chemistry Research

, Volume 16, Issue 3, pp 101–111 | Cite as

Substituted aminoalcohol ester analogs of indomethacin with reduced toxic effects

  • Parmeshwari K. Halen
  • Kewal K. Chagti
  • Rajani Giridhar
  • Mange Ram YadavEmail author
Original Research

Abstract

Synthesis and evaluation of five different N,N-disubstituted aminoethanol ester derivatives of indomethacin bearing structural resemblance to the aminoethanol ester class of anticholinergics are reported herein. The anticholinergic activity was incorporated into the intact esters to overcome the gastric toxicity of indomethacin, not only by blocking the acidic functionality but also by decreasing gastric secretions and motility. These derivatives exhibited in vitro stability in buffers of pH 2.0 and 7.4 for 6 h and were readily hydrolyzed by human plasma esterases to liberate the parent drug. All the derivatives were significantly less irritating to the gastric mucosa than the parent drug. Though only two esters showed antiinflammatory activity similar to that of the parent drug at equivalent dose levels, all the esters were equipotent to indomethacin in the mouse acetic acid–induced writhing assay for analgesic action. The present evaluation indicates that the combined pharmacological properties of these ester derivatives may prove useful for design and development of novel gastric sparing antiinflammatory molecules with potentially important therapeutic applications.

Keywords

Antiinflammatory Indomethacin Ulceration 

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Notes

Acknowledgments

The authors thank AICTE (All India Council of Technical Education), New Delhi for providing financial support through a research grant (TAPTEC Major Research Project).

References

  1. Abordo EA, Bowden K, Huntington AP, Powell SL (1998) Prodrugs. Part 3. 2-Formylphenyl esters of indomethacin, ketoprofen and ibuprofen and 6-substituted 2-formyl and 2-acylphenyl esters of aspirin. Il Farmaco 53:95PubMedCrossRefGoogle Scholar
  2. Akira Y, Tadashi F (1992) Possible mechanisms of gastroduodenal mucosal damage in volunteers treated with Non-steroidal antiinflammatory drugs: the usefulness of prodrugs. J Rheumatol 19:1075Google Scholar
  3. Bonina FP, Montenegro L, De Capraris P, Bousquet E, Tirendi S (1991) 1-Alkylazacyclo alkan-2-one esters have prodrugs of indomethacin for improved delivery through human skin. Int J Pharm 77:21CrossRefGoogle Scholar
  4. Bonina FP, Pugila C, Santagati NA, Saija A, Tomino A, Tita B (2002) Oligoethylene ester derivatives of ketoprofen, naproxen and diclofenac as oral prodrugs: a pharmacological evaluation. Pharmazie 57:552PubMedGoogle Scholar
  5. Halen PK, Chagti KK, Giridhar R, Yadav MR (2006) Synthesis and pharmacological evaluation of some dual-acting aminoalcohol ester derivatives of Flurbiprofen and 2-[1,1- Biphenyl-4-yl]acetic Acid: A potential approach to reduce local gastrointestinal toxicity. Chem Biodiversity 3:1238CrossRefGoogle Scholar
  6. Halen PK, Raval MK, Chagti KK, Giridhar R, Yadav MR (2007) Synthesis and evaluation of some gastrointestinal sparing anti-inflammatory aminoethyl ester derivatives of naphthalene-based NSAIDs. Arch Pharm Chem Life Sci 340:88CrossRefGoogle Scholar
  7. Holmberg K, Hansen B (1979) Ester synthesis with dicyclohexylcarbodiimide improved by acid catalysts. Acta Chem Scand B 33:410CrossRefGoogle Scholar
  8. Kalgutkar AS, Crews BC, Slaeh S, Prudhomme D, Marnett LJ (2005) Indolyl esters and amides related to indomethacin are selective COX-2 inhibitors. Biol Med Chem 13:6810CrossRefGoogle Scholar
  9. Khanna S, Madam M, Vangoori A, Banerjee R, Thaimattam R, Jafar Sadik Basha SK, Mullangi R, Casturi SR, Pal M (2006) Evaluation of glycolamide esters of indomethacin as potential cyclooxygenase-2 (COX-2) inhibitors. Biol Med Chem 14:4820CrossRefGoogle Scholar
  10. Koster R, Anderson M (1959) Acetic acid for Analgesic Screening. J Fed Proc 18:412Google Scholar
  11. Lattin DL, Fifer EK (1981) Drugs affecting cholinergic neurotransmission. In: Williams DA (ed) Foye's principles of medicinal chemistry, 5th edn. Williams & Wilkins, Philadelphia, p 269Google Scholar
  12. Mahfouz NM, Omar FA, Aboul-Fadl T (1999) Cyclic amide derivatives as potential prodrugs II: N-Hydroxymethyl succinimde-/isatin esters of some NSAIDs as prodrugs with an improved therapeutic index. Eur J Med Chem 34:551PubMedGoogle Scholar
  13. Parmar NS, Desai J (1993) A review of the current methodology for the evaluation of gastric and duodenal anti-ulcer agents. K Indian J Pharmacol 25:120Google Scholar
  14. Paul AD, Shah E, Richard MM, Peter J (2004) Lessons from the withdrawal of Rofecoxib. Br Med J 329:867CrossRefGoogle Scholar
  15. Scheen AJ (2004) Withdrawal of Rofecoxib (Vioxx): What about cardiovascular safety of cycloxygenase selective non-steroidal anti-inflammatory drugs? Rev Med Liege 59:5650Google Scholar
  16. Takeuchi T (1989) Bilateral adrenalectomy worsens gastric mucosal lesions induced by indomethacin in the rat. Role of enhanced gastric motility. Clin Rep 8:167Google Scholar
  17. Ueda I, Ishii K, Arai H, Ikeda S, Hitomi Y, Hatanaka M (1991) Design, synthesis and anti- inflammatory activity of new indomethacin ester 2-[N-{3-(3-piperidinomethyl)phenoxy) propyl carbamoylmethylthio]ethyl 1-(p-chlorobenzoyl)-5-methoxy-2-methyl-indole-3-acetate. Chem Pharm Bull 39:697Google Scholar
  18. Van Rossum JM, Hurkmans JH, Walters CJ (1965) Cumulative dose response curves. J Arch Int Pharmacodyn Ther 143:299Google Scholar
  19. Wallace JL, Cirino G (1994) The development of gastrointestinal-sparing nonsteroidal anti- inflammatory drugs. Trends Pharmacol Sci 15:405PubMedCrossRefGoogle Scholar
  20. Winter CA, Risley EA, Nuss GW (1962) Carrageenan-induced edema in hind paw of the rat as an assay. Proc Soc Exp Biol Med 111:544PubMedGoogle Scholar
  21. Yadav MR, Halen PK, Chagti KK, Hemalata B, Giridhar R (2005) A novel approach towards therapeutic optimization of diclofenac. Ars Pharm 46:263Google Scholar

Copyright information

© Birkha¨user Boston 2007

Authors and Affiliations

  • Parmeshwari K. Halen
    • 1
  • Kewal K. Chagti
    • 1
  • Rajani Giridhar
    • 1
  • Mange Ram Yadav
    • 1
    Email author
  1. 1.Pharmacy Department, Faculty of Technology and Engineering, KalabhavanThe M.S. University of BarodaVadodaraIndia

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